4-[4-(2-fluorobenzyl)-4-hydroxy-piperidin-1-yl]-benzoic acid ethyl ester | 870812-22-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-[4-(2-fluorobenzyl)-4-hydroxy-piperidin-1-yl]-benzoic acid ethyl ester
• 英文别名: ethyl 4-(4-(2-fluorobenzyl)-4-hydroxy-1-piperidinyl)benzoate；ethyl 4-[4-[(2-fluorophenyl)methyl]-4-hydroxypiperidin-1-yl]benzoate
• CAS: 870812-22-9
• 化学式: C₂₁H₂₄FNO₃
• 分子量: 357.425
• InChiKey: QEDNUFMIXSVVLH-UHFFFAOYSA-N

物化性质

• 沸点：
  510.7±50.0 °C(Predicted)
• 密度：
  1?+-.0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-[4-(2-fluorobenzyl)-4-hydroxy-piperidin-1-yl]-benzoic acid ethyl ester 在 4-二甲氨基吡啶 、 lithium hydroxide 、 sodium hydride 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 14.0h， 生成 N-[(4-{[(2R)-4-(dimethylamino)-1-(phenylsulfanyl)butan-2-yl]amino}-3-nitrobenzene)sulfonyl]-4-{4-[(2-fluorophenyl)methyl]-4-methoxypiperidin-1-yl}benzamide
  参考文献：
  名称：

  Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL

  摘要：

  Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

  DOI：

  10.1021/jm061152t
• 作为产物：
  描述：

  4-(4-氧代哌啶-1-基)苯甲酸乙酯 、 magnesium,1-fluoro-2-methanidylbenzene,chloride 以 四氢呋喃 、 乙醚 为溶剂， 生成 4-[4-(2-fluorobenzyl)-4-hydroxy-piperidin-1-yl]-benzoic acid ethyl ester
  参考文献：
  名称：

  Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL

  摘要：

  Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.

  DOI：

  10.1021/jm061152t

文献信息

• N-sulfonylcarboximidamide apoptosis promoters
  申请人：Elmore W. Steven

  公开号：US20050272744A1

  公开（公告）日：2005-12-08

  Compounds having the formula are apoptosis promoters. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

  具有该公式的化合物是凋亡促进剂。还公开了制备这些化合物的方法、含有这些化合物的组合物以及使用这些化合物的治疗方法。
• N-SULFONYLCARBOXIMIDAMIDE APOPTOSIS PROMOTERS
  申请人：Elmore Steven W.

  公开号：US20100035879A1

  公开（公告）日：2010-02-11

  Compounds having the formula are apoptosis promoters. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.

  具有公式的化合物是凋亡促进剂。还公开了制备这些化合物的方法、含有这些化合物的组合物以及使用这些化合物的治疗方法。
• US7585858B2
  申请人：——

  公开号：US7585858B2

  公开（公告）日：2009-09-08
• Studies Leading to Potent, Dual Inhibitors of Bcl-2 and Bcl-xL
  作者：Milan Bruncko、Thorsten K. Oost、Barbara A. Belli、Hong Ding、Mary K. Joseph、Aaron Kunzer、Darlene Martineau、William J. McClellan、Michael Mitten、Shi-Chung Ng、Paul M. Nimmer、Tilman Oltersdorf、Cheol-Min Park、Andrew M. Petros、Alexander R. Shoemaker、Xiaohong Song、Xilu Wang、Michael D. Wendt、Haichao Zhang、Stephen W. Fesik、Saul H. Rosenberg、Steven W. Elmore

  DOI：10.1021/jm061152t

  日期：2007.2.1

  Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide.